Peripherally restricted viral challenge elevates extracellular glutamate and enhances synaptic transmission in the hippocampus

Hunsberger, Holly C.; Wang, Desheng; Petrisko, Tiffany J; Alhowail, Ahmad; Setti, Sharay E.; Suppiramaniam, Vishnu; Konat, G.; Reed, Miranda N.

doi:10.1111/jnc.13665

Cited by 18 publications

(25 citation statements)

References 71 publications

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“…, SAL) was approximately threefold higher than the level observed in mice anesthetized with isoflurane (Hunsberger et al . ). This is congruent with previous studies in rats that revealed approximately threefold higher levels in the striatum of freely moving versus anesthetized animals while the respective increase for the cortex was approximately 30‐fold (Rutherford et al .…”

Section: Discussionmentioning

confidence: 97%

“…However, this increase was only approximately threefold, in contrast to approximately 10‐fold increase in anesthetized mice (Hunsberger et al . ). The cause of this divergence is likely to involve complex neuromodulatory mechanism that might be dependent on the tonic levels of extracellular glutamate.…”

Section: Discussionmentioning

confidence: 97%

“…Briefly, the electrodes obtained from Quanteon (Nicholasville, KY, USA) were coated with glutamate oxidase and calibrated as previously demonstrated in Hunsberger et al . (). To modify the MEA for recording in freely moving awake animals, the MEA paddle was shortened and attached to a miniature omnetics connector (Omnetics Connector Corporation; Minneapolis, MN, USA) to create a pedestal.…”

Section: Methodsmentioning

confidence: 97%

“…Moreover, using the enzyme‐based microelectrode array (MEA) technique, we have shown that PIC challenge robustly upsurges extracellular glutamate levels in the hippocampus (Hunsberger et al . ). Although this finding indicated a plausible role of tonic glutamate in the development of seizure hypersusceptible phenotype, this notion could not have been tested since the measurements were performed in anesthetized animals.…”

mentioning

confidence: 97%

“…Recently, we have shown (Hunsberger et al . ) that PIC challenge profoundly increases excitability of neuronal networks in the hippocampus, the ictal site for KA‐induced seizures (Ben‐Ari and Cossart ). Moreover, using the enzyme‐based microelectrode array (MEA) technique, we have shown that PIC challenge robustly upsurges extracellular glutamate levels in the hippocampus (Hunsberger et al .…”

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confidence: 99%

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Peripheral viral challenge elevates extracellular glutamate in the hippocampus leading to seizure hypersusceptibility

Hunsberger

Konat

Reed

2017

Journal of Neurochemistry

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Peripheral viral infections increase seizure propensity and intensity in susceptible individuals. We have modeled this comorbidity by demonstrating that the acute phase response (APR) instigated by an intraperitoneal (i.p.) injection of a viral mimetic, polyinosinic-polycytidylic acid (PIC), induces protracted hypersusceptibility to kainic-acid (KA)-induced seizures. We have further demonstrated that PIC challenge robustly increases the level of tonic extracellular glutamate and neuronal excitability in the hippocampus. The present study was undertaken to determine a relationship between tonic glutamate and seizure susceptibility following PIC challenge. Briefly, glutamate-sensing microelectrodes were permanently implanted into the CA1 of eight-week old female C57BL/6 mice. Following a three day recovery, APR was induced by i.p. injection of 12 mg/kg of PIC, while saline-injected mice served as controls. Tonic glutamate was measured at 1, 2, 3 and 4 days after PIC challenge. PIC challenge induced an approximately 4-fold increase in tonic glutamate levels measured after 24 h. The levels gradually declined to the baseline values within four days. 24 h after PIC challenge, the mice featured an approximately 3-fold increase in cumulative seizure scores and 2-fold increase in the duration of status epilepticus induced by subcutaneous (s.c.) injection of 12 mg/kg of KA. Seizure scores positively correlated with pre-seizure tonic glutamate. Moreover, seizures resulted in a profound (76%) elevation of extracellular glutamate in the CA1 of PIC-challenged but not saline-injected mice. Our results implicate the increase of extracellular glutamate as a mediator of seizure hypersusceptibility induced by peripheral viral challenge.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 97%

mentioning

confidence: 97%

mentioning

confidence: 99%

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Peripheral viral challenge elevates extracellular glutamate in the hippocampus leading to seizure hypersusceptibility

Hunsberger

Konat

Reed

2017

Journal of Neurochemistry

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Hippocampal Glutamate Levels and Their Correlation With Subregion Volume in School‐Aged Children With MRI‐Negative Epilepsy: A Preliminary Study

Xu,

Ren,

Liu

et al. 2024

Magnetic Resonance Imaging

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BackgroundAbnormal levels of glutamate constitute a key pathophysiologic mechanism in epilepsy. The use of glutamate chemical exchange saturation transfer (GluCEST) imaging to measure glutamate levels in pediatric epilepsy is rarely reported in research.PurposeTo investigate hippocampal glutamate level variations in pediatric epilepsy and the correlation between glutamate and hippocampal subregional volumes.Study TypeCross‐sectional, prospective.SubjectsA total of 38 school‐aged pediatric epilepsy patients with structurally normal MRI as determined by at least two independent radiologists (60% males; 8.7 ± 2.5 years; including 20 cases of focal pediatric epilepsy [FE] and 18 cases of generalized pediatric epilepsy [GE]) and 17 healthy controls (HC) (41% males; 9.0 ± 2.5 years).Field Strength/Sequence3.0 T; 3D magnetization prepared rapid gradient echo (MPRAGE) and 2D turbo spin echo GluCEST sequences.AssessmentThe relative concentration of glutamate was calculated through pixel‐wise magnetization transfer ratio asymmetry (MTRasym) analysis of the GluCEST data. Hippocampal subfield volumes were computed from MPRAGE data using FreeSurfer.Statistical TestsThis study used t tests, one‐way analysis of variance, Kruskal–Wallis tests, and Pearson correlation analysis. P < 0.05 was considered statistically significant.ResultsThe MTRasym values of both the left and right hippocampi were significantly elevated in GE (left: 2.51 ± 0.23 [GE] vs. 2.31 ± 0.12 [HCs], right: 2.50 ± 0.22 [GE] vs. 2.27 ± 0.22 [HCs]). The MTRasym values of the ipsilateral hippocampus were significantly elevated in FE (2.49 ± 0.28 [ipsilateral] vs. 2.29 ± 0.16 [HCs]). The MTRasym values of the ipsilateral hippocampus were significantly increased compared to the contralateral hippocampus in FE (2.49 ± 0.28 [ipsilateral] vs. 2.35 ± 0.34 [contralateral]). No significant differences in hippocampal volume were found between different groups (left hippocampus, P = 0.87; right hippocampus, P = 0.87).Data ConclusionGluCEST imaging have potential for the noninvasive measurement of glutamate levels in the brains of children with epilepsy.Level of Evidence2Technical EfficacyStage 1

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Peripheral viral challenge triggers hippocampal production of inflammatory proteins

Petrisko

Konat

2017

Metab Brain Dis

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Peripheral viral infections increase seizure propensity and intensity in susceptible individuals. We have modeled this comorbidity by demonstrating that intraperitoneal (ip) injection of the conventional viral mimetic, polyinosinic-polycytidylic acid (PIC), renders the brain hypersusceptible to seizures induced by kainic acid (KA). At the molecular level, the hippocampus, which is the ictal site of KA-induced seizures, exhibits upregulated expression of messages encoding several inflammatory genes. Here, we profiled temporal expression of these genes at the protein level. Briefly, eight-week old female C57BL/6 mice were ip injected with 12 mg/kg of PIC and inflammatory proteins were quantified in the hippocampus and blood by ELISA. We found a robust but transient increase in blood concentration of IL-6, CXCL10, CCL2, CXCL9, CCL7 and CCL12 six hours after PIC challenge. CXCL1, IL1β, TNFα and CXCL2 featured a moderate increase. However, only four chemokines were increased in the hippocampus. CXCL10 showed the highest increase 6-12 h after PIC challenge, and its level dwindled to the baseline by 48 h. CXCL1, CXCl9 and CXCL2 were also transiently elevated but their maximal values were by an order of magnitude lower than the values for CXCL10. These results indicate that CXCL10 is the primary inflammatory protein generated in the hippocampus in response to PIC challenge, and that this chemokine may drive the development of seizure hypersusceptibility. In addition, the hippocampus featured a protracted increase in the levels of anaphylatoxins C3a and C5a, indicating the activation of the complement cascades.

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Peripherally restricted viral challenge elevates extracellular glutamate and enhances synaptic transmission in the hippocampus

Cited by 18 publications

References 71 publications

Peripheral viral challenge elevates extracellular glutamate in the hippocampus leading to seizure hypersusceptibility

Peripheral viral challenge elevates extracellular glutamate in the hippocampus leading to seizure hypersusceptibility

Hippocampal Glutamate Levels and Their Correlation With Subregion Volume in School‐Aged Children With MRI‐Negative Epilepsy: A Preliminary Study

Peripheral viral challenge triggers hippocampal production of inflammatory proteins

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